Different Genes Interact with Particulate Matter and Tobacco Smoke Exposure in Affecting Lung Function Decline in the General Population
Identifieur interne : 000628 ( Pmc/Checkpoint ); précédent : 000627; suivant : 000629Different Genes Interact with Particulate Matter and Tobacco Smoke Exposure in Affecting Lung Function Decline in the General Population
Auteurs : Ivan Curjuric [Suisse] ; Medea Imboden [Suisse] ; Rachel Nadif [France] ; Ashish Kumar [Suisse, Royaume-Uni] ; Christian Schindler [Suisse] ; Margot Haun [Autriche] ; Florian Kronenberg [Autriche] ; Nino Künzli [Suisse] ; Harish Phuleria [Suisse] ; Dirkje S. Postma [Pays-Bas] ; Erich W. Russi [Suisse] ; Thierry Rochat [Suisse] ; Florence Demenais [France] ; Nicole M. Probst-Hensch [Suisse]Source :
- PLoS ONE [ 1932-6203 ] ; 2012.
Abstract
Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes.
We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures.
For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV1), FEV1 over forced vital capacity (FEV1/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF25-75) was regressed on interval exposure to particulate matter <10 µm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (pinteraction<0.05). Replication was attempted for SNPs with MAF>10% in 3320 SAPALDIA participants without GWAS.
On the SNP-level, rs2035268 in gene SNCA accelerated FEV1/FVC decline by 3.8% (pinteraction = 2.5×10−6), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml pinteraction = 9.7×10−8) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (pinteraction = 3.0×10−4) on FEV1/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful.
Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobacco smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challenging.
Url:
DOI: 10.1371/journal.pone.0040175
PubMed: 22792237
PubMed Central: 3391223
Affiliations:
- Autriche, France, Pays-Bas, Royaume-Uni, Suisse
- Angleterre, Canton de Zurich, Groningue (province), Oxfordshire, Île-de-France
- Groningue, Oxford, Paris, Zurich
- Université d'Oxford
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PMC:3391223Le document en format XML
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<author><name sortKey="Probst Hensch, Nicole M" sort="Probst Hensch, Nicole M" uniqKey="Probst Hensch N" first="Nicole M." last="Probst-Hensch">Nicole M. Probst-Hensch</name>
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<country xml:lang="fr">Suisse</country>
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<author><name sortKey="Imboden, Medea" sort="Imboden, Medea" uniqKey="Imboden M" first="Medea" last="Imboden">Medea Imboden</name>
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<author><name sortKey="Haun, Margot" sort="Haun, Margot" uniqKey="Haun M" first="Margot" last="Haun">Margot Haun</name>
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<author><name sortKey="Kronenberg, Florian" sort="Kronenberg, Florian" uniqKey="Kronenberg F" first="Florian" last="Kronenberg">Florian Kronenberg</name>
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</nlm:aff>
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<author><name sortKey="Kunzli, Nino" sort="Kunzli, Nino" uniqKey="Kunzli N" first="Nino" last="Künzli">Nino Künzli</name>
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</affiliation>
</author>
<author><name sortKey="Phuleria, Harish" sort="Phuleria, Harish" uniqKey="Phuleria H" first="Harish" last="Phuleria">Harish Phuleria</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute SwissTPH, Basel, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute SwissTPH, Basel</wicri:regionArea>
<wicri:noRegion>Basel</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>University of Basel, Basel, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>University of Basel, Basel</wicri:regionArea>
<wicri:noRegion>Basel</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Postma, Dirkje S" sort="Postma, Dirkje S" uniqKey="Postma D" first="Dirkje S." last="Postma">Dirkje S. Postma</name>
<affiliation wicri:level="3"><nlm:aff id="aff7"><addr-line>Department of Pulmonary Medicine and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Pulmonary Medicine and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen</wicri:regionArea>
<placeName><settlement type="city">Groningue</settlement>
<region nuts="2" type="province">Groningue (province)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Russi, Erich W" sort="Russi, Erich W" uniqKey="Russi E" first="Erich W." last="Russi">Erich W. Russi</name>
<affiliation wicri:level="3"><nlm:aff id="aff8"><addr-line>Division of Pulmonary Medicine, University Hospital Zürich, Zürich, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Division of Pulmonary Medicine, University Hospital Zürich, Zürich</wicri:regionArea>
<placeName><settlement type="city">Zurich</settlement>
<region nuts="3" type="region">Canton de Zurich</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rochat, Thierry" sort="Rochat, Thierry" uniqKey="Rochat T" first="Thierry" last="Rochat">Thierry Rochat</name>
<affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Division of Pulmonary Medicine, Geneva University Hospitals, Geneva, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Division of Pulmonary Medicine, Geneva University Hospitals, Geneva</wicri:regionArea>
<wicri:noRegion>Geneva</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Demenais, Florence" sort="Demenais, Florence" uniqKey="Demenais F" first="Florence" last="Demenais">Florence Demenais</name>
<affiliation wicri:level="3"><nlm:aff id="aff10"><addr-line>INSERM, U946, Genetic Variation and Human Diseases Unit, Paris, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM, U946, Genetic Variation and Human Diseases Unit, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff11"><addr-line>Fondation Jean Dausset - Centre d’Etude du Polymorphisme Humain (CEPH), Paris, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Fondation Jean Dausset - Centre d’Etude du Polymorphisme Humain (CEPH), Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff12"><addr-line>Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Paris, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Probst Hensch, Nicole M" sort="Probst Hensch, Nicole M" uniqKey="Probst Hensch N" first="Nicole M." last="Probst-Hensch">Nicole M. Probst-Hensch</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute SwissTPH, Basel, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute SwissTPH, Basel</wicri:regionArea>
<wicri:noRegion>Basel</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>University of Basel, Basel, Switzerland</addr-line>
</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>University of Basel, Basel</wicri:regionArea>
<wicri:noRegion>Basel</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS ONE</title>
<idno type="eISSN">1932-6203</idno>
<imprint><date when="2012">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes.</p>
</sec>
<sec><title>Objectives</title>
<p>We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures.</p>
</sec>
<sec><title>Methods</title>
<p>For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV<sub>1</sub>
), FEV<sub>1</sub>
over forced vital capacity (FEV<sub>1</sub>
/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF<sub>25-75</sub>
) was regressed on interval exposure to particulate matter <10 µm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p<sub>interaction</sub>
<0.05). Replication was attempted for SNPs with MAF>10% in 3320 SAPALDIA participants without GWAS.</p>
</sec>
<sec><title>Results</title>
<p>On the SNP-level, rs2035268 in gene SNCA accelerated FEV<sub>1</sub>
/FVC decline by 3.8% (p<sub>interaction</sub>
= 2.5×10<sup>−6</sup>
), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p<sub>interaction</sub>
= 9.7×10<sup>−8</sup>
) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p<sub>interaction</sub>
= 3.0×10<sup>−4</sup>
) on FEV<sub>1</sub>
/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful.</p>
</sec>
<sec><title>Conclusions</title>
<p>Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobacco smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challenging.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group><journal-title>PLoS ONE</journal-title>
</journal-title-group>
<issn pub-type="epub">1932-6203</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">22792237</article-id>
<article-id pub-id-type="pmc">3391223</article-id>
<article-id pub-id-type="publisher-id">PONE-D-11-21280</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0040175</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology</subject>
<subj-group><subject>Computational Biology</subject>
<subj-group><subject>Genomics</subject>
<subj-group><subject>Genome Analysis Tools</subject>
<subj-group><subject>Genetic Networks</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Population Genetics</subject>
<subj-group><subject>Genetic Polymorphism</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Genetics</subject>
<subj-group><subject>Human Genetics</subject>
<subj-group><subject>Genetic Association Studies</subject>
</subj-group>
</subj-group>
<subj-group><subject>Genetics of Disease</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject>
<subj-group><subject>Epidemiology</subject>
<subj-group><subject>Environmental Epidemiology</subject>
<subject>Epidemiological Methods</subject>
<subject>Genetic Epidemiology</subject>
</subj-group>
</subj-group>
<subj-group><subject>Public Health</subject>
<subj-group><subject>Environmental Health</subject>
</subj-group>
</subj-group>
<subj-group><subject>Pulmonology</subject>
<subj-group><subject>Smoking Related Disorders</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Different Genes Interact with Particulate Matter and Tobacco Smoke Exposure in Affecting Lung Function Decline in the General Population</article-title>
<alt-title alt-title-type="running-head">PM10 and Tobacco Differently Affect Lung Function</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Curjuric</surname>
<given-names>Ivan</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Imboden</surname>
<given-names>Medea</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nadif</surname>
<given-names>Rachel</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Ashish</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schindler</surname>
<given-names>Christian</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Haun</surname>
<given-names>Margot</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kronenberg</surname>
<given-names>Florian</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Künzli</surname>
<given-names>Nino</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Phuleria</surname>
<given-names>Harish</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Postma</surname>
<given-names>Dirkje S.</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Russi</surname>
<given-names>Erich W.</given-names>
</name>
<xref ref-type="aff" rid="aff8"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rochat</surname>
<given-names>Thierry</given-names>
</name>
<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Demenais</surname>
<given-names>Florence</given-names>
</name>
<xref ref-type="aff" rid="aff10"><sup>10</sup>
</xref>
<xref ref-type="aff" rid="aff11"><sup>11</sup>
</xref>
<xref ref-type="aff" rid="aff12"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Probst-Hensch</surname>
<given-names>Nicole M.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute SwissTPH, Basel, Switzerland</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>University of Basel, Basel, Switzerland</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>INSERM, U1018, CESP Centre for research in Epidemiology and Population Health, Respiratory and Environmental Epidemiology Team, Villejuif, France</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Université Paris-Sud 11, UMRS 1018, Villejuif, France</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line>
</aff>
<aff id="aff6"><label>6</label>
<addr-line>Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria</addr-line>
</aff>
<aff id="aff7"><label>7</label>
<addr-line>Department of Pulmonary Medicine and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands</addr-line>
</aff>
<aff id="aff8"><label>8</label>
<addr-line>Division of Pulmonary Medicine, University Hospital Zürich, Zürich, Switzerland</addr-line>
</aff>
<aff id="aff9"><label>9</label>
<addr-line>Division of Pulmonary Medicine, Geneva University Hospitals, Geneva, Switzerland</addr-line>
</aff>
<aff id="aff10"><label>10</label>
<addr-line>INSERM, U946, Genetic Variation and Human Diseases Unit, Paris, France</addr-line>
</aff>
<aff id="aff11"><label>11</label>
<addr-line>Fondation Jean Dausset - Centre d’Etude du Polymorphisme Humain (CEPH), Paris, France</addr-line>
</aff>
<aff id="aff12"><label>12</label>
<addr-line>Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Paris, France</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Dubé</surname>
<given-names>Marie-Pierre</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">Universite de Montreal, Canada</aff>
<author-notes><corresp id="cor1">* E-mail: <email>Nicole.Probst@unibas.ch</email>
</corresp>
<fn fn-type="con"><p>Analyzed the data: IC MI NMPH CS. Wrote the paper: IC NMPH MI. Data collection and study design: NMPH MI CS NK TR. Analysis design: IC MI NMPH CS RN. Critical revision and contribution to interpretation: RN AK MH FK NK HP DSP EWR TR FD.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2012</year>
</pub-date>
<pub-date pub-type="epub"><day>6</day>
<month>7</month>
<year>2012</year>
</pub-date>
<volume>7</volume>
<issue>7</issue>
<elocation-id>e40175</elocation-id>
<history><date date-type="received"><day>28</day>
<month>10</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>6</day>
<month>6</month>
<year>2012</year>
</date>
</history>
<permissions><copyright-statement>Curjuric et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</copyright-statement>
<copyright-year>2012</copyright-year>
</permissions>
<abstract><sec><title>Background</title>
<p>Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes.</p>
</sec>
<sec><title>Objectives</title>
<p>We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures.</p>
</sec>
<sec><title>Methods</title>
<p>For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV<sub>1</sub>
), FEV<sub>1</sub>
over forced vital capacity (FEV<sub>1</sub>
/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF<sub>25-75</sub>
) was regressed on interval exposure to particulate matter <10 µm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p<sub>interaction</sub>
<0.05). Replication was attempted for SNPs with MAF>10% in 3320 SAPALDIA participants without GWAS.</p>
</sec>
<sec><title>Results</title>
<p>On the SNP-level, rs2035268 in gene SNCA accelerated FEV<sub>1</sub>
/FVC decline by 3.8% (p<sub>interaction</sub>
= 2.5×10<sup>−6</sup>
), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p<sub>interaction</sub>
= 9.7×10<sup>−8</sup>
) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p<sub>interaction</sub>
= 3.0×10<sup>−4</sup>
) on FEV<sub>1</sub>
/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful.</p>
</sec>
<sec><title>Conclusions</title>
<p>Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobacco smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challenging.</p>
</sec>
</abstract>
<counts><page-count count="11"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Autriche</li>
<li>France</li>
<li>Pays-Bas</li>
<li>Royaume-Uni</li>
<li>Suisse</li>
</country>
<region><li>Angleterre</li>
<li>Canton de Zurich</li>
<li>Groningue (province)</li>
<li>Oxfordshire</li>
<li>Île-de-France</li>
</region>
<settlement><li>Groningue</li>
<li>Oxford</li>
<li>Paris</li>
<li>Zurich</li>
</settlement>
<orgName><li>Université d'Oxford</li>
</orgName>
</list>
<tree><country name="Suisse"><noRegion><name sortKey="Curjuric, Ivan" sort="Curjuric, Ivan" uniqKey="Curjuric I" first="Ivan" last="Curjuric">Ivan Curjuric</name>
</noRegion>
<name sortKey="Curjuric, Ivan" sort="Curjuric, Ivan" uniqKey="Curjuric I" first="Ivan" last="Curjuric">Ivan Curjuric</name>
<name sortKey="Imboden, Medea" sort="Imboden, Medea" uniqKey="Imboden M" first="Medea" last="Imboden">Medea Imboden</name>
<name sortKey="Imboden, Medea" sort="Imboden, Medea" uniqKey="Imboden M" first="Medea" last="Imboden">Medea Imboden</name>
<name sortKey="Kumar, Ashish" sort="Kumar, Ashish" uniqKey="Kumar A" first="Ashish" last="Kumar">Ashish Kumar</name>
<name sortKey="Kumar, Ashish" sort="Kumar, Ashish" uniqKey="Kumar A" first="Ashish" last="Kumar">Ashish Kumar</name>
<name sortKey="Kunzli, Nino" sort="Kunzli, Nino" uniqKey="Kunzli N" first="Nino" last="Künzli">Nino Künzli</name>
<name sortKey="Kunzli, Nino" sort="Kunzli, Nino" uniqKey="Kunzli N" first="Nino" last="Künzli">Nino Künzli</name>
<name sortKey="Phuleria, Harish" sort="Phuleria, Harish" uniqKey="Phuleria H" first="Harish" last="Phuleria">Harish Phuleria</name>
<name sortKey="Phuleria, Harish" sort="Phuleria, Harish" uniqKey="Phuleria H" first="Harish" last="Phuleria">Harish Phuleria</name>
<name sortKey="Probst Hensch, Nicole M" sort="Probst Hensch, Nicole M" uniqKey="Probst Hensch N" first="Nicole M." last="Probst-Hensch">Nicole M. Probst-Hensch</name>
<name sortKey="Probst Hensch, Nicole M" sort="Probst Hensch, Nicole M" uniqKey="Probst Hensch N" first="Nicole M." last="Probst-Hensch">Nicole M. Probst-Hensch</name>
<name sortKey="Rochat, Thierry" sort="Rochat, Thierry" uniqKey="Rochat T" first="Thierry" last="Rochat">Thierry Rochat</name>
<name sortKey="Russi, Erich W" sort="Russi, Erich W" uniqKey="Russi E" first="Erich W." last="Russi">Erich W. Russi</name>
<name sortKey="Schindler, Christian" sort="Schindler, Christian" uniqKey="Schindler C" first="Christian" last="Schindler">Christian Schindler</name>
<name sortKey="Schindler, Christian" sort="Schindler, Christian" uniqKey="Schindler C" first="Christian" last="Schindler">Christian Schindler</name>
</country>
<country name="France"><noRegion><name sortKey="Nadif, Rachel" sort="Nadif, Rachel" uniqKey="Nadif R" first="Rachel" last="Nadif">Rachel Nadif</name>
</noRegion>
<name sortKey="Demenais, Florence" sort="Demenais, Florence" uniqKey="Demenais F" first="Florence" last="Demenais">Florence Demenais</name>
<name sortKey="Demenais, Florence" sort="Demenais, Florence" uniqKey="Demenais F" first="Florence" last="Demenais">Florence Demenais</name>
<name sortKey="Demenais, Florence" sort="Demenais, Florence" uniqKey="Demenais F" first="Florence" last="Demenais">Florence Demenais</name>
<name sortKey="Nadif, Rachel" sort="Nadif, Rachel" uniqKey="Nadif R" first="Rachel" last="Nadif">Rachel Nadif</name>
</country>
<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Kumar, Ashish" sort="Kumar, Ashish" uniqKey="Kumar A" first="Ashish" last="Kumar">Ashish Kumar</name>
</region>
</country>
<country name="Autriche"><noRegion><name sortKey="Haun, Margot" sort="Haun, Margot" uniqKey="Haun M" first="Margot" last="Haun">Margot Haun</name>
</noRegion>
<name sortKey="Kronenberg, Florian" sort="Kronenberg, Florian" uniqKey="Kronenberg F" first="Florian" last="Kronenberg">Florian Kronenberg</name>
</country>
<country name="Pays-Bas"><region name="Groningue (province)"><name sortKey="Postma, Dirkje S" sort="Postma, Dirkje S" uniqKey="Postma D" first="Dirkje S." last="Postma">Dirkje S. Postma</name>
</region>
</country>
</tree>
</affiliations>
</record>
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